DESCRIPTION (Applicant's Description): This project will be executed at the Foothills Campus of Colorado State University by Wendy A. Pott, D.V.M. Dr. Pott's long-term goals involve integrating the disciplines of pathology, toxicology and biomedical engineering in the realm of cancer research. Her immediate goals involve investigating the roles of three common groundwater contaminants, individually and in combination, in the development of hepatic angiosarcoma. The research career development plan Dr. Pott will follow involves an interdisciplinary background of coursework and practical implementation of knowledge and development of skills in the laboratory and in the mathematical modelling arena. The long-term objectives of this project are 1) to evaluate the carcinogenic effects of sub-chronic exposure to three common groundwater contaminants-arsenic, vinyl chloride and 1,2-dichloroethane (1,2-DCE) - implicated as etiologic agents in the development of angiosarcoma; and 2) to use data from these studies with physiologically-based pharmacokinetic/pharmacodynamic (PB-PK/PD) models and statistical and mathematical modelling techniques for the purpose of health risk characterization. The specific aims of this project are 1) to determine the extent to which arsenic alone will act to induce the development of angiosarcoma; 2) to evaluate whether synergistic carcinogenic activity may result when arsenic is combined with vinyl chloride and/or 1,2-DCE; 3) to develop PB-PK/PD models for target tissue dosimetry of single chemicals and combinations of chemicals following exposure to arsenic, vinyl chloride, and/or 1,2-DCE; and 4) to develop cell turnover and carcinogenesis models and integrate them with PB-PK/PD models to characterize cancer risks associated with exposure to arsenic, vinyl chloride and/or 1,2-DCE. These goals will be accomplished using a medium-term angiosarcoma bioassay to investigate the effects of each of the above-mentioned chemicals alone and in combination in inducing hepatic angiosarcoma. Data gathered from these experiments will be used to develop models to determine cancer risks and safe drinking water levels of these chemicals.